Project 4 is focused on testing the safety of novel inhaled mucolytic compounds in persons with asthma (specific aim 1), testing these in an allergen challenge model of acute exacerbation in mild mite allergic asthmatics (specific aim 2), and examining the effect of such compounds on mucociliary clearance (MCC) and lung function in moderate asthmatics on stable controller therapy over a 2-week period (specific aim 3). Studies from our group indicate that S-S bonds are a key element in increased viscosity of mucus in asthma and have catalyzed the study of thiol based mucolytics for asthma in this tPPG. The best candidate for this intervention is P2176, a di-thiol mucolytic which has robust ability to degrade mucins in sputum samples from asthmatics in vitro, has been well tolerated in animals in pre-clinical studies, and is currently in Phase I studies of healthy volunteers. Safety studies of P2176 in asthmatics will be the major focus in years 1-2. In years 2-5, we will begin to screen mite-allergic asthmatics for late phase responsiveness to mite allergen, and begin to pursue aims 2 and 3.
Specific Aim 2 will examine the effect of P2176 on an allergen-induced late phase response, which we have shown is associated with increased mucus secretion and decreased MCC. Success with SA2 would suggest a role for mucolytics in acute exacerbation of asthma.
Specific Aim 3 will examine the effect of 2 weeks daily treatment on MCC in volunteers with moderate asthma. If successful, this study would indicate the P2176 has a role in maintenance therapy for asthma in persons with long term mucus-derived airway obstruction.

Public Health Relevance

The proposed research will investigate whether novel inhaled mucolytics can improve mucus transport and reduce airways obstruction in asthma. If successful, this research may significantly accelerate the development of therapies that improve the health of patients with airways diseases, including CF, chronic bronchitis, and asthma.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Sheridan, John T
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Chapel Hill
United States
Zip Code
Abdullah, Lubna H; Coakley, Raymond; Webster, Megan J et al. (2018) Mucin Production and Hydration Responses to Mucopurulent Materials in Normal versus Cystic Fibrosis Airway Epithelia. Am J Respir Crit Care Med 197:481-491
Yu, Dongfang; Saini, Yogesh; Chen, Gang et al. (2018) Loss of ? Epithelial Sodium Channel Function in Meibomian Glands Produces Pseudohypoaldosteronism 1-Like Ocular Disease in Mice. Am J Pathol 188:95-110
Muhlebach, Marianne S; Hatch, Joseph E; Einarsson, Gisli G et al. (2018) Anaerobic bacteria cultured from cystic fibrosis airways correlate to milder disease: a multisite study. Eur Respir J 52:
Livraghi-Butrico, Alessandra; Wilkinson, Kristen J; Volmer, Allison S et al. (2018) Lung disease phenotypes caused by overexpression of combinations of ?-, ?-, and ?-subunits of the epithelial sodium channel in mouse airways. Am J Physiol Lung Cell Mol Physiol 314:L318-L331
Chen, Gang; Volmer, Allison S; Wilkinson, Kristen J et al. (2018) Role of Spdef in the Regulation of Muc5b Expression in the Airways of Naive and Mucoobstructed Mice. Am J Respir Cell Mol Biol 59:383-396
Bennett, William D; Zeman, Kirby L; Laube, Beth L et al. (2018) Homogeneity of Aerosol Deposition and Mucociliary Clearance are Improved Following Ivacaftor Treatment in Cystic Fibrosis. J Aerosol Med Pulm Drug Deliv 31:204-211
Ge, Ting; Grest, Gary S; Rubinstein, Michael (2018) Nanorheology of Entangled Polymer Melts. Phys Rev Lett 120:057801
Wagner, Caroline E; Turner, Bradley S; Rubinstein, Michael et al. (2017) A Rheological Study of the Association and Dynamics of MUC5AC Gels. Biomacromolecules 18:3654-3664
Donoghue, Lauren J; Livraghi-Butrico, Alessandra; McFadden, Kathryn M et al. (2017) Identification of trans Protein QTL for Secreted Airway Mucins in Mice and a Causal Role for Bpifb1. Genetics 207:801-812
Ribeiro, Carla M P; Lubamba, Bob A (2017) Role of IRE1?/XBP-1 in Cystic Fibrosis Airway Inflammation. Int J Mol Sci 18:

Showing the most recent 10 out of 76 publications